The limbic system is an integrated brain area involved in the regulation of reward, motivation, emotional expression, and memory. These regions are considered critical to the development and persistence of addiction. In our currently-funded proposal, the regional cerebral blood flow (rCBF) response to the limbicstimulant procaine was assessed relative to saline in cocaine-addicted subjects (n=38) and healthy controls (n=37). Our findings revealed that cocaine-addicted men and women exhibit a blunted limbic rCBF response to procaine compared to age and gender matched controls. Procaine, unlike cocaine, has minimal interaction with the monoamine transporters, but has potent affinity with both cholinergic and 5HT3 receptors. Preclinical studies indicate that these latter receptor systems are altered following the acute and chronic administration of cocaine, and disruptions in these systems may modulate subsequent drug reinforcement. Our competitive renewal is designed to further elucidate the putative neurobiologic differences in the cholinergic and 5HT3 systems revealed by procaine. Hypotheses: We hypothesize that cocaine-addicted subjects will demonstrate impairment of the cholinergic and 5HT3 receptor systems. Preliminary Studies: To explore cholinergic and 5HT3 receptor functioning, healthy controls (n=3) and cocaine-addicted subjects (n=3) were administered (1) the cholinergic agonist physostigmine, (2) the muscarinic cholinergic antagonist scopolamine, (3) the 5HT3 antagonist ondansetron, and (4) saline. Preliminary analyses suggest that the limbic rCBF response (relative to saline) following all three probes is blunted in cocaine-addicted subjects compared to controls. Methods: Male (n=12) and female (n=12) cocaine-addicted subjects between two and six weeks abstinence will be compared to age and gender matched controls (12 male and 12 female). All subjects will receive physostigmine, scopolamine, ondansetron, and saline. Single photon emission computed tomography (SPECT) and SPM analytic techniques will be used to assess rCBF and differences within and between groups. Significance: The cholinergic and 5HT3 receptor systems have not previously been studied in cocaine-addicted subjects using neuroimaging techniques. Our competing renewal will be used to identify specific changes in these neuroreceptor systems, providing avenues for new pharmacologic investigations in the treatment of cocaine dependence.